PulmCrit: We should engineer a new crystalloid

Introduction

Considering the importance of crystalloid in critical care, one might expect crystalloid composition to be meticulously engineered and updated. However, our crystalloid choices remain archaic. Normal saline and Lactated Ringers (LR) were developed in the 1800s, whereas Plasmalyte and Normosol emerged in the 1970s.

This post explores how a new crystalloid could be designed, based on modern critical care concepts. The point isn't necessarily the precise formulation of the proposed crystalloid, but rather that it's time to consider something new. Continuing to debate the merits of NS vs. LR or Plasmalyte may be repeating the wrong question.

Problems with existing crystalloids

All available crystalloids have some drawbacks:

Normal saline: This acidotic, hyperchloremic, and hypertonic fluid is the least physiologic. Although believed to be safe in hyperkalemia, NS has actually been shown to increase potassium levels due to intracellular shifts induced by acidosis. The ongoing use of normal saline exemplifies status quo bias. Of course, normal saline remains perfect for a couple of patients a year: patients with hyponatremia, hypokalemia, and metabolic alkalosis due to profound vomiting:

Plasmalyte & Normosol: The drawback of these solutions is their use of gluconate and acetate:

Gluconate: There is little rationale for including gluconate in intravenous fluid. Gluconate doesn’t appear to be metabolized by the human body, but instead appears to be excreted unchanged in the urine. It might even act as an osmotic diuretic.

Acetate: Unlike gluconate, acetate is metabolized to yield bicarbonate, so it functions as the alkali in Plasmalyte and Normosol. However, acetate is a poor alkali. Acetate was previously used as an alkali in dialysis fluid, but this was discontinued because it caused hypotension. In an animal model of hemorrhagic shock, infusion of plasmalyte increased mortality compared to LR (p = 0.02; Traverso 1986)(1):

the pro-inflammatory, vasodilatory, myocardial depressant, and hypoxemia promoting properties of acetate led to its removal from contemporary renal replacement fluids. –Davies 2011

Lactated Ringers (LR): This is generally my preferred crystalloid, but it has some drawbacks. It is hypotonic, which could be problematic in patients with elevated intracranial pressure. The inclusion of calcium limits its compatibility with blood transfusion and certain medications.

Giving any crystalloid will tend to pull the serum chemistries toward the chemical properties of the crystalloid. For example, consider the effect of LR on potassium. LR has a potassium concentration of 4 mM. Therefore, if LR is given to a patient with a hypokalemia (i.e. 2 mM), it will tend to increase the potassium. Alternatively, if LR is given to a patient with a hyperkalemia (i.e. 6 mM), it will tend to decrease the potassium. Therefore, whatever potassium abnormality may exist (hyperkalemia or hypokalemia), the LR will tend to correct it (2).

In general, when we are constructing a general-purpose crystalloid it makes sense to design the crystalloid to match our target serum concentrations of various ions. Thus, whatever abnormality the patient may have, crystalloid infusion will pull them closer to target serum concentrations. This allows us to safely infuse such fluid into patients whose chemistries we don’t know: regardless of the patient’s derangement, our crystalloid will pull them closer to target. This sort of general-purpose crystalloid might not be the ideal approach to fix the problem, but at least we can be confident that it won’t exacerbate it (3).

Properties of an ideal crystalloid?

1. Isotonic

An ideal crystalloid should probably be isotonic. This would allow bolusing in patients with increased intracranial pressure without concerns regarding hypotonicity. Additionally, this would tend to pull the tonicity towards normal, based on the target principle.

2. Sodium lactate used as an anion

Historically lactate has been feared, because it is often associated with badness. However, the lactate molecule itself is beneficial. Lactate is a physiologic anion which the body has evolved to utilize as fuel in times of stress. For example, a concentrated solution of sodium lactate has been proven to improve cardiac function (Nalos 2014, Fontaine 2014). Among the various anions included in crystalloid (gluconate, acetate, lactate), lactate is supported by the greatest evidence regarding safety and benefit.

3. Normokalemic

As discussed above, the potassium concentration should be set to an intermediate level of 4 mEq/L (similar to LR).

4. High-normal magnesium concentration

Hospitalized patients usually have hypomagnesemia, which may increase their risk for arrhythmia. One strength of plasmalyte and normosol is the inclusion of magnesium, reducing the need for additional magnesium supplementation. This has been shown to be cost-saving (Smith 2014)(4).

An ideal solution would include a magnesium concentration slightly above the upper limit of normal (1.5 mM, equal to 3.6 mg/dL). Although this might seem a bit high, magnesium levels in this range are entirely safe and potentially desirable. For example, among patients undergoing treatment for atrial fibrillation, a magnesium level of 3.6-4.9 mg/dL may be considered to be the “therapeutic” target range. In practice, this fluid wouldn’t increase the patient’s magnesium level all the way to 3.6 mg/dL, but it would be more effective at increasing the patient’s magnesium to a reasonable level.

5. Normochloremic

6. No calcium

LR was designed with a calcium concentration close to physiologic levels. This may be a design flaw for several reasons:

Including calcium in intravenous fluid causes incompatibility with blood transfusion and certain drugs.

Giving intravenous calcium usually only causes only a transient increase in the calcium level (5). LR contains a tiny amount of calcium (one liter contains the equivalent of one tenth of a gram of calcium chloride), so it is doubtful that this could have lasting effects on serum calcium level. Even in animal studies comparing large infusions of normal saline vs. LR, no differences in serum calcium were found (Martini 2013).

Critically ill patients are often hypocalcemic, but this doesn't appear to cause harm. Hypocalcaemia could represent a natural protective mechanism or merely an epiphenomenon of severe illness (e.g. similar to sick euthyroid syndrome). Attempting to raise calcium levels could be harmful, except in cases of iatrogenic hypocalcaemia (e.g. massive transfusion; Aberegg 2016).

My ideal crystalloid

Based on the above goals, my ideal crystalloid would be composed as above. This winds up being largely a hybrid of LR and plasmalyte, combining the advantages of both fluids.

One potential problem with this fluid could be that it is slightly alkalinizing (with a strong ion difference of 34 mEq/L)(6). This is an indirect consequence of being unable to reproduce the anion gap with exogenous albumin (7). However, this shouldn’t be a problem for many reasons:

My ideal crystalloid (SID 34 mEq/L) is only trivially more alkalinizing than LR (SID 28 mEq/L). For example, the effect of one liter of ideal crystalloid on pH is equivalent to the effect of one liter of LR plus one tenth of an ampule of sodium bicarbonate (8).

All patients receive at least some normal saline (e.g. used to keep IV lines open and mix drugs). Since normal saline is an acidotic fluid with a strong ion difference of zero, the simultaneous administration of normal saline and ideal crystalloid would likely cancel each other out, with little net impact on the patient’s pH.

Where is the evidence?

Crystalloid is among the most commonly used drugs in critical care. This creates a paradox: the clinical consequences of crystalloid design out-strip our ability to study them. For example, imagine that adding magnesium reduced the rate of new-onset atrial fibrillation by 0.2% (NNT = 500). This difference would be too small to detect using a RCT (10). However, considering that millions of patients are treated with crystalloid, this difference could nonetheless affect the outcome of thousands of patients (11).

Lacking RCT evidence, the next-best approach is to design a crystalloid based on indirect and physiological evidence. For example, consider the following:

(B) Clinicians are often uncomfortable if the patient is significantly academic. Sometimes, interventions are performed to maintain the patient's pH (e.g. dialysis, sodium bicarbonate, ventilator adjustments).

It is debatable whether treating acidemia (B) is beneficial. Regardless, it is logically inconsistent to perform a large-volume resuscitation with normal saline (A) and then treat the resulting acidemia (B). There are only two logically coherent approaches to large-volume fluid resuscitation and pH:

Coherent approach #1: Infuse normal saline, don't monitor pH, and refuse to make any intervention based on the pH or bicarbonate levels.

The best approach is unknown, so it could be reasonable to perform an RCT comparing approach #1 versus approach #2. However, there is little need for an RCT to demonstrate that it is illogical to cause an acidosis (A) and then treat it (B).

A similar argument supports the addition of magnesium to crystalloid. If we are going to measure magnesium levels and replete magnesium, then it is logically consistent to supplement crystalloid with magnesium.

Cost differences are trivial

One argument used to support the use of normal saline is that it is the cheapest. However, the cost differential between LR or normosol versus normal saline is low (<< 1$/liter)(12). Based on the potential to reduce other costs (e.g. magnesium supplementation, occasional avoidance of dialysis)(13), more “expensive” crystalloids are likely to be cost-neutral or cost-saving.

Currently available fluids were all designed before 1980, prior to a modern understanding of electrolyte and lactate metabolism.

Saline, LR, and plasmalyte all have some room for improvement.

Given that crystalloid is administered to millions of patients, even subtle changes could have an effect on some patients.

It might be time to engineer a new crystalloid, designed to combine the strengths of LR and plasmalyte.

Related posts about electrolytic obsession

Notes

This could also relate to some effect of gluconate (the physiology of which remains quite mysterious). Regardless of the mechanism, this study raises concerns about plasmalyte.

In practice, this effect is very small for potassium, because absolute differences in potassium concentration are low.

Of course, once the patient’s serum chemistries are known, it may be wise to choose an aphysiologic solution to intentionally affect the patient’s chemistries (e.g. isotonic bicarbonate to correct a non-anion-gap metabolic acidosis). This concept is discussed further in the section on pH-guided resuscitation.

As discussed below, the cost differential between different crystalloids is low. In contrast, the material and nursing cost associated with purchasing and infusing separate bags of magnesium is likely to be higher.

A patient with hypokalemia or hypomagnesemia may often have a total-body deficiency of potassium or magnesium, so it makes some sense to administer potassium or magnesium. In contrast, critically ill patients with hypocalcemia have more complex physiology involving re-distribution of calcium out of the blood. Therefore, treating them with exogenous calcium doesn't seem to work very well – it isn't treating the underlying physiologic problem.

The strong ion difference (SID) of a fluid is the best way to predict the effect it will have on the body’s pH. A fluid with SID ~24 mEq/L will have little effect on the pH or tend to pull it towards normal. A fluid with SID <24 mEq/L (e.g. normal saline, with a SID of zero) will be acidifying. Alternatively, a fluid with SID >24 mEq/L (e.g. isotonic bicarbonate, with a SID of 150 mEq/L) will be alkalinizing. My ideal crystalloid has a SID of 34 mEq/L, which would tend to be slightly alkalinizing.

When trying to design a crystalloid that mimics the physiology of blood, the anion gap becomes problematic. Normally the anion gap is largely composed of albumin and phosphate. These cannot be contained in designer crystalloids due to refrigeration and precipitation issues. This makes it difficult to achieve the following three tasks simultaneously: maintain normal osmolality, maintain a normal chloride content, and maintain a normal strong ion difference. Consider, for example, LR and Plasmalyte. LR manages to maintain a normal chloride concentration, at the cost of a slightly elevated strong ion difference (28 mEq/L) and hypotonicity. Plasmalyte gets around this issue by the inclusion of gluconate, but it is questionable whether this “filler” is a physiologically sound approach. My ideal crystalloid approaches the anion gap conundrum by accepting a slightly higher strong ion difference than normal.

The SID difference between LR and my ideal crystalloid is 6 mEq/L. This is equivalent to 6 ml of 1M sodium bicarbonate, which is nearly one tenth (5 ml) of a standard “amp” of bicarbonate (50 ml of 1 M sodium bicarbonate).

Incidentally, this data may also suggest that not all alkali are created equal. As discussed above, sodium lactate seems to fare better in clinical trials than sodium bicarbonate or sodium acetate.

In order to be adequately powered to identify an effect size this low, a study would need to recruit a vast number of patients.

This is an interesting example of a therapy that could be beneficial despite having a very high NNT (i.e. NNT=500). Generally speaking, if a drug had a NNT of 500, it wouldn't make sense to prescribe it. However, millions of patients need some form of crystalloid. Thus, a minor tweak to crystalloid design could be justified even if it had a very high NNT, because the patients are going to receive crystalloid anyway – it's simply a matter of which formulation.

Actual prices vary depending on various negotiations between hospitals and manufacturer. In my limited experience, the absolute difference in cost of these crystalloids is very small.

One of the indications for dialysis is metabolic acidosis. It is well established that balanced crystalloids induce less metabolic acidosis than normal saline. It stands to reason that occasionally, the use of balanced crystalloids (as opposed to normal saline) could tip a patient towards avoidance of dialysis. How frequently this may occur is debatable. However, given the cost of dialysis, even if this occurs very rarely it could justify the increased cost of balanced crystalloids.

(1) Yeah, the effect of 4 mM K is probably more cosmetic than anything else. I think the clinically relevant point is that containing 4 mM of potassium isn’t contraindicated in hyperkalemia. The only meaningful effect that these fluids have on potassium is due to shifting of potassium as a result of changes in pH (e.g. NS increases potassium due to induction of an acidosis – this has been shown in RCTs).

That said, I still think that adding calcium to IV fluid causes compatibility issues (e.g. with some medications) without any clear benefit.

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2 years ago

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Hon

In my institution and practice in the OR, it’s fine to run LR after a pack of RBC. We do not see any clots in the filter even when the LR is trickled in. I believe this is because there is generally excess citrate in the pack of RBC which mops up the tiny amount of calcium in LR.

I considered adding phosphate, but it seems to cause problems regarding incompatibility with various fluids and medications. The “ideal crystalloid” is built off ions which are used in LR and plasmalyte, and seem to be fairly soluble players (not tending to cause compatibility problems). This isn’t the case with phosphate, so I think if you added phosphate it would eventually lead to compatibility headaches.

Love it! This makes me want to break into someone’s lab and mix some up tonight.

Seriously though… it seems like every time I open up the New England Journal there is a study about some new designer drug or monoclonal antibody. In comparison, creating new crystalloid is extremely easy.

Malcolm Fisher OA famously claimed he could resuscitate a patient with dog piss (unpublished personal communication) and I sort of agree. Give a broad spread of anions and cations alongside the water and most patients can sort out the homeostasis.

Tom Woodcock, Independent Consultant living in Stockbridge, Hampshire. The Tom Woodcock PhD living in Burlington, Vermont is my son.

Thank you for a very thoughtful post. A few comments: (1) I would not recommend resuscitation with dog piss. However, this would certainly resolve any concerns you may have regarding hypotonicity (dog urine seems to average ~1500 mOsm). (2) Regarding the target osmolality of the fluid, I would still argue that we should target an isotonic fluid. A recent article reported that over time the incidence of hypernatremia in critically ill patients has increased, to the point where patients are now evenly balanced between hyponatremia and hypernatremia (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794471/). This shift may be related to the use of more fluid-conservative strategies and increased diuretic use recently. In a setting where patients are roughly balanced between hyponatremia and hypernatremia, then targeting an isotonic fluid is reasonable. This also may avoid unwanted rapid osmotic shifts when bolusing fluids. (3) Thanks for pointing out the osmolarity vs. osmolality difference. You’re right – the “ideal crystalloid” above will likely end up being slightly hypotonic. This could be remedied by adding ~8 mM of NaCl. This would leave the fluid a tad hyperchloremic, but I suppose nothing is perfect not even “ideal crystalloid.”

agree with all that, I wonder if Malcolms dingos were peeing something different to your average Vermont dog? I think my main point is we need a “first bag” to hang which harms no-one in a dose up to two litres, followed by an individualised prescription which we can mix from the basic bags (eg sodium chloride, sodium bicarbonate, Dextrose, sodium lactate). My local DIY store has a machine that mixes paints to make exactly the color you want, how about a machine that infuses a custom-blended intravenous solution to our patients?

yeah, Vermont dogs may be especially hypertonic at this time of year. It’s very hot, so they’re probably losing a lot of free water from all the panting. Agree that we need to design a fluid that can be blindly given without harming anyone. However, I would argue that this should be “ideal crystalloid” for the following reasons: (1) Some patients with severe metabolic acidosis may be harmed by two liters saline. I have seen this a few times, mostly in severe DKA (more here: http://emcrit.org/pulmcrit/four-dka-pearls/). Nothing terrible happened, but it seems foolish to admit a patient with a bicarb of 7 mEq/L and then push their bicarb into the unmeasurably low range (our lab simply reports out “<5 mEq/L"). (2) Some patients with severe hyperkalemia might be harmed by two liters of saline due to causing acidosis and potassium shift (more here: http://emcrit.org/pulmcrit/myth-busting-lactated-ringers-is-safe-in-hyperkalemia-and-is-superior-to-ns/). Currently I use LR for this, but LR could theoretically harm patients with elevated ICP. By tweaking the osmolality to a normal range, "ideal crystalloid" could potentially be the fluid that you could give to any patient in the hospital and not hurt them (assuming of course that they need fluid).

I used to advocate 1L NSal/ 500 NaBic 1.26% alternating, but DKA is so safely treated with insulin and just Hamburger that I really don’t see the point in complicating the effective treatment of a common condition; QJM 2012 Apr. 105:337-43. 10.1093/qjmed/hcr226. “This study failed to indicate benefit from using Ringer’s lactate solution compared to 0.9% sodium chloride solution regarding time to normalization of pH in patients with DKA. The time to reach a blood glucose level of 14 mmol/l took significantly longer with the Ringer’s lactate solution.”
I do worry that Hamburger-bashing as an intellectual bit of fun for us experts could end up deterring first responders outside of our ivory towers. Please don’t put doubts in their mind; Hamburger alone for days on end is of course a sign of an uncritical (dangerous?) prescriber, but Hamburger used intelligently with other solutions can produce better results; Raghunathan K, Bonavia A, Nathanson BH et al. Association between Initial Fluid Choice and Subsequent In-hospital Mortality during the Resuscitation of Adults with Septic Shock. Anesthesiology. 2015;123:1385-1393. Bags of fluid don’t harm patients, its uncritical or unreasoned fluid prescribing that kills. And colloids…

My thoughts on the Van Zyl study are located here: http://emcrit.org/pulmcrit/four-dka-pearls/ The data on LR isn’t great, but the data on plasmalyte is a bit better. Overall the use of a balanced crystalloid will minimize acidosis by avoiding a hyperchloremic non-AG metabolic acidosis. As far as DKA goes, I agree that giving normal saline is probably safe in that it’s not going to kill the patient. Normal saline may not have much impact on the first 6-8 hours of DKA treatment. Realisticaly I think the biggest problem with normal saline in DKA occurs on the back end, after the ketoacidosis has resolved. Metabolic acidosis increases insulin resistance, which may make it harder for patients to stay out of DKA once they’ve improved. I’ve seen a series of cases over the last few years where the patient improved, normalized their anion gap and ketosis, the bicarb increased to the 15-18 mEq/L range, and then after stopping the insulin infusion the patient slipped *back* into DKA. It is possible that leaving the patient with a hyperchloremic metabolic acidosis could increase the risk of recurrent DKA & delayed recovery. I agree that we shouldn’t be dogmatic about fluid selection, and my goal certainly… Read more »